Rare germline variants are associated with rapid biochemical recurrence after radical prostate cancer treatment: a PPCG study

Daniel Burns; Ezequiel Anokian; Edward J. Saunders; Robert G. Bristow; Michael Fraser; Jüri Reimand; Thorsten Schlomm; Guido Sauter; Benedikt Brors; Jan Korbel; Joachim Weischenfeldt; Sebastian M. Waszak; Niall M. Corcoran; Chol-Hee Jung; Bernard J. Pope; Chris M. Hovens; Géraldine Cancel-Tassin; Olivier Cussenot; Massimo Loda; Chris Sander; Vanessa M. Hayes; Karina Dalsgaard Sorensen; Yong-Jie Lu; Freddie C. Hamdy; Christopher S. Foster; Vincent Gnanapragasam; Adam Butler; Andy G. Lynch; Charlie E. Massie; CR-UK/Prostate Cancer UK, ICGC, The PPCG; Dan J. Woodcock; Colin S. Cooper; David C. Wedge; Daniel S. Brewer; Zsofia Kote-Jarai; Rosalind A. Eeles

doi:10.1016/j.eururo.2022.05.007

Rare germline variants are associated with rapid biochemical recurrence after radical prostate cancer treatment: a PPCG study

Daniel Burns, Ezequiel Anokian, Edward J. Saunders, Robert G. Bristow, Michael Fraser, Jüri Reimand, Thorsten Schlomm, Guido Sauter, Benedikt Brors, Jan Korbel, Joachim Weischenfeldt, Sebastian M. Waszak, Niall M. Corcoran, Chol-Hee Jung, Bernard J. Pope, Chris M. Hovens, Géraldine Cancel-Tassin, Olivier Cussenot, Massimo Loda, Chris SanderVanessa M. Hayes, Karina Dalsgaard Sorensen, Yong-Jie Lu, Freddie C. Hamdy, Christopher S. Foster, Vincent Gnanapragasam, Adam Butler, Andy G. Lynch, Charlie E. Massie, CR-UK/Prostate Cancer UK, ICGC, The PPCG, Dan J. Woodcock, Colin S. Cooper, David C. Wedge, Daniel S. Brewer, Zsofia Kote-Jarai, Rosalind A. Eeles

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Abstract

Background: Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression.

Objective: To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa, and understand the genetic factors associated with such progression.

Design, Setting and Participants: Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG consortium) from UK, Canada, Germany, Australia and France. Findings were validated using 383 patients from The Cancer Genome Atlas (TCGA).
Outcome Measurements and Statistical analysis: 15,822 rare (MAF<1%) predicted-deleterious coding germline mutations were identified. Optimal multifactor and univariate Cox regression models were built to predict time to BCR after radical treatment, using germline variants grouped by functionally annotated gene-sets. Models were tested for robustness using bootstrap resampling.

Results: Optimal Cox regression multifactor models showed that rare predicted-deleterious germline variants in “Hallmark” gene-sets were consistently associated with altered time to BCR. Three gene-sets had a statistically significant association with risk-elevated outcome when modelling all samples: PI3K/AKT/mTOR, Inflammatory response and KRAS signalling (up). PI3K/AKT/mTOR and KRAS signalling (up) were also associated among patients with higher grade cancer, as were Pancreas-beta cells, TNFA signalling via NKFB and Hypoxia, the latter of which was validated in the independent TCGA dataset.

Conclusions: We demonstrate for the first time that rare deleterious coding germline variants robustly associate with time to BCR after radical treatment, including cohort-independent validation. Our findings suggest that germline testing at diagnosis could aid clinical decisions by stratifying patients for differential clinical management.

Patient summary: PrCa patients with particular genetic mutations have a higher chance of relapsing after initial radical treatment, potentially providing opportunities to identify which patients might need additional treatments earlier.

Original language	English
Pages (from-to)	201-211
Number of pages	11
Journal	European Urology
Volume	82
Issue number	2
Early online date	31 May 2022
DOIs	https://doi.org/10.1016/j.eururo.2022.05.007
Publication status	Published - Aug 2022

Keywords

Biochemical recurrence
Germline variants
Pan Prostate Cancer Group
Prostate cancer

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Burns, D., Anokian, E., Saunders, E. J., Bristow, R. G., Fraser, M., Reimand, J., Schlomm, T., Sauter, G., Brors, B., Korbel, J., Weischenfeldt, J., Waszak, S. M., Corcoran, N. M., Jung, C.-H., Pope, B. J., Hovens, C. M., Cancel-Tassin, G., Cussenot, O., Loda, M., ... Eeles, R. A. (2022). Rare germline variants are associated with rapid biochemical recurrence after radical prostate cancer treatment: a PPCG study. European Urology, 82(2), 201-211. https://doi.org/10.1016/j.eururo.2022.05.007

@article{18b9d14b5ce74aa382cab5f061b300bc,

title = "Rare germline variants are associated with rapid biochemical recurrence after radical prostate cancer treatment: a PPCG study",

abstract = "Background: Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression. Objective: To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa, and understand the genetic factors associated with such progression. Design, Setting and Participants: Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG consortium) from UK, Canada, Germany, Australia and France. Findings were validated using 383 patients from The Cancer Genome Atlas (TCGA). Outcome Measurements and Statistical analysis: 15,822 rare (MAF<1%) predicted-deleterious coding germline mutations were identified. Optimal multifactor and univariate Cox regression models were built to predict time to BCR after radical treatment, using germline variants grouped by functionally annotated gene-sets. Models were tested for robustness using bootstrap resampling. Results: Optimal Cox regression multifactor models showed that rare predicted-deleterious germline variants in “Hallmark” gene-sets were consistently associated with altered time to BCR. Three gene-sets had a statistically significant association with risk-elevated outcome when modelling all samples: PI3K/AKT/mTOR, Inflammatory response and KRAS signalling (up). PI3K/AKT/mTOR and KRAS signalling (up) were also associated among patients with higher grade cancer, as were Pancreas-beta cells, TNFA signalling via NKFB and Hypoxia, the latter of which was validated in the independent TCGA dataset. Conclusions: We demonstrate for the first time that rare deleterious coding germline variants robustly associate with time to BCR after radical treatment, including cohort-independent validation. Our findings suggest that germline testing at diagnosis could aid clinical decisions by stratifying patients for differential clinical management. Patient summary: PrCa patients with particular genetic mutations have a higher chance of relapsing after initial radical treatment, potentially providing opportunities to identify which patients might need additional treatments earlier.",

keywords = "Biochemical recurrence, Germline variants, Pan Prostate Cancer Group, Prostate cancer",

author = "Daniel Burns and Ezequiel Anokian and Saunders, {Edward J.} and Bristow, {Robert G.} and Michael Fraser and J{\"u}ri Reimand and Thorsten Schlomm and Guido Sauter and Benedikt Brors and Jan Korbel and Joachim Weischenfeldt and Waszak, {Sebastian M.} and Corcoran, {Niall M.} and Chol-Hee Jung and Pope, {Bernard J.} and Hovens, {Chris M.} and G{\'e}raldine Cancel-Tassin and Olivier Cussenot and Massimo Loda and Chris Sander and Hayes, {Vanessa M.} and {Dalsgaard Sorensen}, Karina and Yong-Jie Lu and Hamdy, {Freddie C.} and Foster, {Christopher S.} and Vincent Gnanapragasam and Adam Butler and Lynch, {Andy G.} and Massie, {Charlie E.} and {CR-UK/Prostate Cancer UK, ICGC, The PPCG} and Woodcock, {Dan J.} and Cooper, {Colin S.} and Wedge, {David C.} and Brewer, {Daniel S.} and Zsofia Kote-Jarai and Eeles, {Rosalind A.}",

year = "2022",

month = aug,

doi = "10.1016/j.eururo.2022.05.007",

language = "English",

volume = "82",

pages = "201--211",

journal = "European Urology",

issn = "0302-2838",

publisher = "Elsevier",

number = "2",

}

Burns, D, Anokian, E, Saunders, EJ, Bristow, RG, Fraser, M, Reimand, J, Schlomm, T, Sauter, G, Brors, B, Korbel, J, Weischenfeldt, J, Waszak, SM, Corcoran, NM, Jung, C-H, Pope, BJ, Hovens, CM, Cancel-Tassin, G, Cussenot, O, Loda, M, Sander, C, Hayes, VM, Dalsgaard Sorensen, K, Lu, Y-J, Hamdy, FC, Foster, CS, Gnanapragasam, V, Butler, A, Lynch, AG, Massie, CE, CR-UK/Prostate Cancer UK, ICGC, The PPCG, Woodcock, DJ, Cooper, CS, Wedge, DC, Brewer, DS, Kote-Jarai, Z & Eeles, RA 2022, 'Rare germline variants are associated with rapid biochemical recurrence after radical prostate cancer treatment: a PPCG study', European Urology, vol. 82, no. 2, pp. 201-211. https://doi.org/10.1016/j.eururo.2022.05.007

TY - JOUR

T1 - Rare germline variants are associated with rapid biochemical recurrence after radical prostate cancer treatment: a PPCG study

AU - Burns, Daniel

AU - Anokian, Ezequiel

AU - Saunders, Edward J.

AU - Bristow, Robert G.

AU - Fraser, Michael

AU - Reimand, Jüri

AU - Schlomm, Thorsten

AU - Sauter, Guido

AU - Brors, Benedikt

AU - Korbel, Jan

AU - Weischenfeldt, Joachim

AU - Waszak, Sebastian M.

AU - Corcoran, Niall M.

AU - Jung, Chol-Hee

AU - Pope, Bernard J.

AU - Hovens, Chris M.

AU - Cancel-Tassin, Géraldine

AU - Cussenot, Olivier

AU - Loda, Massimo

AU - Sander, Chris

AU - Hayes, Vanessa M.

AU - Dalsgaard Sorensen, Karina

AU - Lu, Yong-Jie

AU - Hamdy, Freddie C.

AU - Foster, Christopher S.

AU - Gnanapragasam, Vincent

AU - Butler, Adam

AU - Lynch, Andy G.

AU - Massie, Charlie E.

AU - CR-UK/Prostate Cancer UK, ICGC, The PPCG

AU - Woodcock, Dan J.

AU - Cooper, Colin S.

AU - Wedge, David C.

AU - Brewer, Daniel S.

AU - Kote-Jarai, Zsofia

AU - Eeles, Rosalind A.

PY - 2022/8

Y1 - 2022/8

N2 - Background: Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression. Objective: To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa, and understand the genetic factors associated with such progression. Design, Setting and Participants: Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG consortium) from UK, Canada, Germany, Australia and France. Findings were validated using 383 patients from The Cancer Genome Atlas (TCGA). Outcome Measurements and Statistical analysis: 15,822 rare (MAF<1%) predicted-deleterious coding germline mutations were identified. Optimal multifactor and univariate Cox regression models were built to predict time to BCR after radical treatment, using germline variants grouped by functionally annotated gene-sets. Models were tested for robustness using bootstrap resampling. Results: Optimal Cox regression multifactor models showed that rare predicted-deleterious germline variants in “Hallmark” gene-sets were consistently associated with altered time to BCR. Three gene-sets had a statistically significant association with risk-elevated outcome when modelling all samples: PI3K/AKT/mTOR, Inflammatory response and KRAS signalling (up). PI3K/AKT/mTOR and KRAS signalling (up) were also associated among patients with higher grade cancer, as were Pancreas-beta cells, TNFA signalling via NKFB and Hypoxia, the latter of which was validated in the independent TCGA dataset. Conclusions: We demonstrate for the first time that rare deleterious coding germline variants robustly associate with time to BCR after radical treatment, including cohort-independent validation. Our findings suggest that germline testing at diagnosis could aid clinical decisions by stratifying patients for differential clinical management. Patient summary: PrCa patients with particular genetic mutations have a higher chance of relapsing after initial radical treatment, potentially providing opportunities to identify which patients might need additional treatments earlier.

AB - Background: Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression. Objective: To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa, and understand the genetic factors associated with such progression. Design, Setting and Participants: Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG consortium) from UK, Canada, Germany, Australia and France. Findings were validated using 383 patients from The Cancer Genome Atlas (TCGA). Outcome Measurements and Statistical analysis: 15,822 rare (MAF<1%) predicted-deleterious coding germline mutations were identified. Optimal multifactor and univariate Cox regression models were built to predict time to BCR after radical treatment, using germline variants grouped by functionally annotated gene-sets. Models were tested for robustness using bootstrap resampling. Results: Optimal Cox regression multifactor models showed that rare predicted-deleterious germline variants in “Hallmark” gene-sets were consistently associated with altered time to BCR. Three gene-sets had a statistically significant association with risk-elevated outcome when modelling all samples: PI3K/AKT/mTOR, Inflammatory response and KRAS signalling (up). PI3K/AKT/mTOR and KRAS signalling (up) were also associated among patients with higher grade cancer, as were Pancreas-beta cells, TNFA signalling via NKFB and Hypoxia, the latter of which was validated in the independent TCGA dataset. Conclusions: We demonstrate for the first time that rare deleterious coding germline variants robustly associate with time to BCR after radical treatment, including cohort-independent validation. Our findings suggest that germline testing at diagnosis could aid clinical decisions by stratifying patients for differential clinical management. Patient summary: PrCa patients with particular genetic mutations have a higher chance of relapsing after initial radical treatment, potentially providing opportunities to identify which patients might need additional treatments earlier.

KW - Biochemical recurrence

KW - Germline variants

KW - Pan Prostate Cancer Group

KW - Prostate cancer

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U2 - 10.1016/j.eururo.2022.05.007

DO - 10.1016/j.eururo.2022.05.007

M3 - Article

SN - 0302-2838

VL - 82

SP - 201

EP - 211

JO - European Urology

JF - European Urology

IS - 2

ER -

Rare germline variants are associated with rapid biochemical recurrence after radical prostate cancer treatment: a PPCG study

Abstract

Keywords

UN SDGs

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